“Ribonuclease A: From kcat/KM to the Clinic” will be presented in a special seminar by Ronald T. Raines, Ph.D., Firmenich Professor of Chemistry, Massachusetts Institute of Technology.

The vast majority of extant drugs are small molecules that block the flow of biochemical information. Enzymes also have the potential to disrupt this flow. For example, ribonuclease A, which spawned the first enzymatic reaction mechanism and seminal advances in protein chemistry, is an efficient catalyst of RNA cleavage. We have discovered that this highly cationic enzyme naturally enters the cytosol of mammalian cells. By enabling ribonuclease A to evade a cytosolic inhibitor protein we have endowed it with the ability to cleave cellular RNA and thereby kill human cells. A variety of chemical and biological tools, especially “fluorogenic labels”, have enabled us to reveal the kinetic mechanism by which ribonucleases exert that cytotoxic activity. These ribonucleases have a marked preference for killing cancerous cells due to a nanomolar affinity for Globo H, a cell-surface glycan that is a human cancer antigen. An inhibitor-evading variant of the human homolog of ribonuclease A is in a Phase I clinical trial as a cancer chemotherapeutic agent. To date, 57 patients have been treated with this enzyme at the University of Texas MD Anderson Cancer Center and the University of Wisconsin Carbone Cancer Center. Eleven of these patients achieved stable disease. Thus, decades of research on ribonuclease A are now poised to yield a drug. [This work is supported by grant R01 CA073808.]

Co-Sponsored by UNL Research Council and Nebraska Center for Integrated Biomolecular Communication (NCIBC)

Open to the Public